The biogenesis of bones in mammalian development depends on the balanced acts of bone-building osteoblasts and bone-absorbing osteoclasts. In adulthood, these two types of cells continue to be active during bone remodeling, which is critical for both bone health and calcium homeostasis. Indian Hedgehog (Ihh) is a crucial regulator of bone development and remodeling. Our preliminary studies indicated that Speckle-type POZ protein (Spop), a substrate-recognition subunit of the Cul3 ubiquitin ligase, is a positive regulator of Ihh signaling, osteoblast differentiation and bone development. The goal of this R03 small grant application is to investigate the cellular and molecular basis of this surprising role of Spop in bone development and remodeling. We will work toward two specific aims. First, we will investigate whether the loss of Spop function results in defective osteoblast differentiation, function and osteopenia in developing and adult mice. In a second specific aim, we will investigate whether Spop positively regulates Ihh signaling through proteasomal degradation of Gli3 repressors. In summary, these studies will provide new insights into the roles of the Speckle-type POZ proteins in bone development and remodeling, and reveal a potential genetic predisposition for osteoporosis.